Update in Pediatric Regional Anesthesia

Regional Anesthesia for Sickle Cell Disease Vaso-occlusive Crisis

By Karla Wyatt, MD, MS  ; Chyong-jy Joyce Liu, DO, MBA, MS
Department of Anesthesiology, Perioperative and Pain Medicine
Texas Children’s Hospital
Baylor College of Medicine
Houston, Texas

Sickle cell disease (SCD) comprises a group of inherited hemoglobinopathies hallmarked by chronic hemolysis and recurrent vaso-occlusive episodes, which can result in multiorgan dysfunction and early mortality.  While the exact incidence is unknown, the Centers for Disease Control and Prevention estimates that there are ~100,000 Americans with SCD, who account for 113,000 annual hospitalizations at an estimated $488 million a year.1-3   The most common sequela associated with SCD is vaso-occlusive crisis. This represents the leading cause of healthcare utilization among patients with the most severe form of SCD (hemoglobin SS).2-3

Vaso-occlusive crisis (VOC) is a severely debilitating manifestation of SCD, associated with unpredictable pain episodes that may or may not have an identifiable trigger.  The presumed paradigm of pathophysiology involves an inciting event that signals a cascade of widespread or localized deoxygenation of hemoglobin S erythrocytes. Resultant intracellular instability via heme auto-oxidation and cytoskeleton disruption yields the characteristic sickled erythrocyte.4 Sickled red blood cells collide with the endothelium upregulating vascular adhesion proteins and interleukins which activate leukocyte recruitment.  Subsequent intravascular polymerization causes insolubility of sickled erythrocytes and leukocytes with sequential micro-vascular occlusion.5 Obstructive vascular clumping with local tissue hypoxia and cyclical reperfusion ischemia is the etiology of VOC mediated pain. In younger children, VOC may manifest as dactylitis occurring in the small bones of the hands and feet, whereas in adolescents the most common sites of pain are the long bones.

Acute pain management for sickle cell patients in VOC is extremely challenging due to the recurrent nature of the disease and limited treatment modalities.  Focused pharmacotherapy targets peripheral and central nociceptive and inflammatory mediated pathways. Early initiation of opioids remains a mainstay, as they are effective at both central and peripheral µ-receptors.6 Unfortunately, opioids carry a multitude of untoward side effects that are particularly undesirable for the SCD population, most notably; sedation, respiratory depression, and atelectasis.  These opioid-related respiratory complications can precipitate hypoxemia and nosocomial respiratory infections, potentially leading to acute chest syndrome. 

A variety of alternative modes of therapy of VOC have been considered. Ketamine and lidocaine have been useful in targeting the N-methyl-D-aspartate (NMDA) receptors while abating the potential opioid-related respiratory complications. Intravenous ketamine antagonizes the NMDA-receptor and inhibits opioid-induced hyperalgesia, thereby reducing opioid consumption and the associated side effects.7,8,9 While ketamine offers favorable analgesia, its use can be limited by sialorrhea, the potential unpleasant experience of hallucinations, and/or euphoria.  Intravenous lidocaine blunts the sympathetic response, inhibits inflammatory cellular recruitment via G-protein coupled pathways and impedes erythrocyte intravascular aggregation.10  The use of non-steroidal anti-inflammatory medications, which have also been employed, can be controversial due to the potential risks of renal dysfunction and worsening sickling.  Investigational studies are ongoing into the role of cannaboids, magnesium, monoclonal antibodies and L-glutamine as VOC therapies via nociceptive pathway interruption, vasodilation, inhibition of cellular adhesion and anti-oxidative properties, respectively.11-14  Non-pharmacologic interventions including cognitive and physical therapy have also proven advantageous for treating VOC pain crisis.2,6,15 Despite these options, a focal antidote that can interrupt the cycle of inflammation, in addition to providing analgesia and local vasodilation is prudent.

The incorporation of regional anesthesia could be instrumental for a subset of patients undergoing VOC pain management.  The utilization of peripheral and central nerve blockades for acute and chronic pain is well established.  With the advancement of ultrasound-guided technology, regional anesthesia can be safely performed in the awake, sedated, or asleep pediatric patient.16 Regional anesthesia delivering local anesthetics can blunt the inflammatory response and promote vasodilation to improve local tissue oxygenation while providing direct anti-nociception.  The evidence for this approach has been demonstrated by Bagry et al., where participants who underwent knee arthroplasty with a continuous peripheral nerve block had a substantial decrease in pain scores, as well as C-reactive protein and leukocyte counts, when compared to those receiving patient-controlled analgesia.10,17  Moreover, a near-infrared spectroscopy prospective analysis illustrated sustained increases in tissue oxygenation in the blocked limb when compared to control, suggesting augmented perfusion following peripheral nerve blockade.18  While there are no prospective, longitudinal, randomized clinical trials investigating the efficacy and safety for regional anesthesia in VOC, the available retrospective literature has shown beneficial outcomes for isolated limb VOC.19-20  Furthermore, there are several reports of successful regional anesthesia applications in pediatric severe acute chest syndrome and preventative perioperative pain crises.21-22  Regional anesthesia as an adjunct to the current therapeutic regimens can interrupt the inflammatory processes, restore perfusion/tissue oxygenation and ameliorate pain, all of which are essential in managing VOC.

As with all clinical decision making, an individualized approach is required when considering the addition of regional anesthesia to the pain regimen of VOC in a patient with SCD. Patient selection is paramount, and in the correct setting, the implementation of this modality is advantageous.  Children and adolescents with isolated limb VOC are ideal candidates for peripheral nerve blocks. Appropriately dosed local anesthetics that facilitate sensory blockade with preservation of function and physical activity through an indwelling nerve block catheter or single dose of medication can significantly reduce opioid consumption and enhance patient rehabilitation.  Multisite regional anesthesia may also be suitable depending upon the rehabilitation goals, site-specific pain, and patient/team expectations.  

Our institutional practice reflects a collaboration between hematology and the acute pain service in determining which patients are best suited for regional consideration.  The overarching goals of care focus on reducing opioid requirements by adequately achieving analgesia at the VOC site(s).  These experiences have demonstrated accelerated return to activities of daily living and ambulation, attenuated parenteral opioid consumption, and increased patient and parental satisfaction.  The repetitive flares of acute pain in SCD can potentially progress to chronic pain states and long term opioid exposure in a vulnerable population.4,6,15  While the existing data is limited, regional anesthesia for VOC may confer benefits of increased patient satisfaction, reduced length of hospital stay, minimization of opioid utilization and ultimate reduction in healthcare costs.

The pediatric sickle cell population brings to the forefront an opportunity for collaboration between medical professionals to mitigate pain, reduce opioid consumption, and facilitate the return of functional status.  Regional anesthesia can provide analgesia, local vasodilation, anti-inflammation, and prevent local tissue hypoxia, all of which are important in the therapeutic strategies for VOC pain.  Pediatric prospective randomized clinical trials exploring the efficacy, safety and the acute or chronic role of regional anesthesia for VOC is pragmatic to enable practitioners to implement the optimum interventions going forward. 


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